In November 2005, HOPES team member Justine Seidenfeld visited the Morimoto Laboratory in the Department of Biochemistry, Molecular Biology and Cell Biology at Northwestern University’s graduate school in Evanston, IL. HOPES would like to thank Dr. Morimoto and the members of his lab for taking time to meet with us and share their outlooks on research and Huntington’s Disease.

The Morimoto Lab studies how cells protect themselves by sensing and responding to environmental and physiologicalstress. These kinds of stress often lead to damage and problems within the cell. Stress can come from a wide variety of sources, like oxidative damage, over heating (heat shock), bacterial infections, and misfolded proteins (For more on proteins and their folding structure, click here) The cell has many different ways of recognizing and responding to stress induced problems. Under normal circumstances the cell can maintain a balanced state known as homeostasis. When stress causes proteins to misfold, the cell responds through a mechanism called the heat shock response. This response increases the amount of molecular chaperones and proteases produced within the cell. Molecular chaperones and proteases correct misfolded proteins, repair damage, and bring the cell back to balance. Sometimes, however, there are so many misfolded proteins that the heat shock response cannot keep up. The misfolded proteins accumulate into protein aggregates. Aggregates are a hallmark of neurodegenerative diseases like HD.

The Morimoto Lab studies the cell’s response to the stress-related buildup of misfolded proteins within the cell. These researchers are attempting to understand the mechanisms that lead to the appearance of misfolded proteins in the cell in the first place. They also study how these misfolded proteins affect the heat shock response, and the consequences for the cell’s overall health.

Dr. Morimoto’s lab looks at HD from the very beginning of the disease cascade. He describes the disease cascade process like this: a protein with an expanded polyglutamine chain (which is toxic) impairs cells and their function over time, eventually leading to nerve cell death. His lab studies the beginning of the cascade, asking the question “What goes wrong in protein quality control?” Dr. Morimoto believes that protein quality control is one of the cell’s most ancient mechanisms. In the very first forms of life, RNA was the main hereditarygenetic material in cells, instead of DNA as it is now. In this “RNA world,” cells were much less complex. In order to survive all of the sources of stress they were subjected to, they must have had very good protein quality control mechanisms. These mechanisms have been preserved in the “DNA world” of the present day. Additionally, the question of protein quality control is especially intriguing because protein misfolding is common among neurodegenerative diseases, HD included. Dr. Morimoto’s findings have the potential to be useful in the study of other neurodegenerative diseases. “The implications are broad,” he says of his research program.

Why does Dr. Morimoto focus on HD if is research is so broad? As he puts it, “HD is a leader as a genetic dominant.” As opposed to some other neurodegenerative diseases, HD is a disease that is easy to identify by using genetics. The presence of at least one allele for the altered Huntingtin gene always indicates a person will have HD. The genetic link is not so clear in other neurodegenerative diseases. For example, only 2% of cases of amyotrophic lateral sclerosis are actually related to an inherited geneticmutation. These cases are called Familial Amyotrophic Lateral Sclerosis, or FALS. In short, using HD to study protein quality control is valuable because it has straightforward genetic links, and it has broader implications for other neurodegenerative diseases.

The Morimoto Lab has also created C. elegansmodels related to tau pathologies, amyotrophic lateral sclerosis, and other polyglutamine diseases besides HD. All of these models help to understand the genetic basis of protein misfolding by comparing the different molecules associated with each of these diseases. In addition to C. elegans, the lab uses use in vitro studies and tissue culture (cells grown in a Petri dish), among others as model systems to answer these questions. Dr. Morimoto describes these multiple approaches as “the only way to run a lab.” These different models allow the lab to run multiple tests on hypotheses, so they can be much more confident about their results. For example, Dr. Morimoto says that there are certain advantages to doing experiments with tissue culture, but that they need to be verified in studies using whole organisms. In doing this, they can see if they get the same in an entire living animal, not just isolated tissue in a Petri dish, and the C. elegans model is a good way to test any hypothesis in his lab.

Dr. Morimoto also discusses the pharmacological studies done in his lab. In these studies, the researchers discover small molecules involved in proteinfolding. These molecules could serve as a basis for therapeutic drugs or therapy treatments. In a large collaborative effort with 26 other laboratories worldwide, the Morimoto lab helped identify a small molecule called celastrol, from a plant often used for its anti-inflammatory properties in Chinese herbal medicine. Celastrol was identified because it can activate important genes involved in the heat shock response and elevate the level of molecular chaperones in the cell. These molecular chaperones could help protect the cell from the damage caused by misfolded proteins. Members of the Morimoto lab are now working with Dr. Richard Silverman, a professor in the Department of Chemistry, to discover the specific structure of celastrol and how it works with other proteins to activate the heat shock response. Dr. Morimoto believes a detailed understanding of exactly how celastrol works is important before it is turned into a therapy drug and put into clinical trials. However, the potential of celastrol certainly seems promising.

Dr. Morimoto discussed his views on the responsibilities of a scientist to the public. “It is our responsibility and obligation to talk to the public about research,” he says. Dr. Morimoto wants patients and their families to understand how research on neurodegenerative disorders works: how scientists pose questions; how drugs and therapies are created; and why animal models like flies, worms, and mice, are used instead of humans at certain stages of the research process.

Dr. Morimoto believes that he and other academic scientists are fortunate because they can choose to focus their research on whatever interests them. They can be well-funded, but that gives them an obligation to educate people on how their money is being spent. Yet not all scientists are trained to do this. Dr. Morimoto believes that more effort is needed to increase communication between laboratory researchers and the public.

Dr. Morimoto is one of the 17 Huntington’s Disease Society of America (HDSA) Coalition for the Cure Senior Researchers. He is committed to long-term HD research and collaborates with other scientists around the world who also study HD. Through the local chapter of the HDSA, HD patients and their families often contact him, and he will sometimes bring them to his lab to meet the postdoctoral fellows, graduate, and undergraduate students working to discover the mechanisms behind HD. Dr. Morimoto says that it helps him get a sense of clarity apart from his research, and he thinks that it is equally beneficial to the patients and their families. He also attends Illinois HDSA meetings to give talks. Since he knows that patients and families are always at these meetings, he tries to make his talks especially relevant for them. One of the great things about science, he says, is that all scientific information is accessible. And the local chapters of the HDSA get scientists to appreciate the public, to make sure that information reaches them in an appropriate way. To learn more about the HDSA, click here.

A unique feature of HD is that it is relatively rare compared to some other neurodegenerative disorders like Alzheimer’s and Parkinson’s (for more information on these diseases, click here). Because less people are affected by HD, there is less funding from the National Institutes of Health (NIH) devoted to HD. Dr. Morimoto says that the community of HD research advocates is amazingly strong and plays a big role is raising necessary money. As an example, he cites the Fiore family of Highwood, IL. The Fiores have a history of HD in their family, and have raised money for HD research by partnering with the HDSA and holding their own fundraising events like golf and poker tournaments (you can visit their site by clicking here). Their work has helped to raise money to open an HDSA Center of Excellence at Rush St. Luke Medical Center in Chicago. According to Dr. Morimoto, families like the Fiores have single-handedly used their personal adversity to “increase awareness of the disease for all.”

Dr. Morimoto received his Ph.D. in molecular biology from the University of Chicago in 1978. He says that he became interested in his line of research when, as a graduate student, he heard a talk by Dr. Matthew Meselson of Harvard University. Dr. Meselson spoke about the newly discovered heat-shock response system in fruit flies. Dr. Morimoto was intrigued by this talk, and did his postdoctoral fellowship at Harvard in Dr. Meselson’s lab. While he was there, he was the first to clone the human Heat-Shock Protein 70 (Hsp70) in 1985, This means that he was the first to discover the location and sequence of the gene that codes for the protein. Now it could be used in genetic studies related to the heat shock response. Hsp70 was identified as a key protein in protein quality control. Multiple studies showed that by making an unusually high amount of Hsp70 in cells prone to protein misfolding, it would suppress the toxic effects of these misfolded proteins. Dr. Morimoto came to Northwestern University in 1982 and continued his research on the heat shock response in neurodegenerative diseases. As he puts it, the 1970s and 80s were full of important discoveries about the regulation of proteinfolding related to the heat-shock response. The 90s brought increasing awareness that neurodegenerative diseases were related to the misfolding of protein aggregates. Seven years ago, his lab began to use C. elegans to study the heat shock response. They began to also study HD in C. elegans, and this is a major portion of his current research. Dr. Morimoto says that his interest in science stemmed from, and continues to be, a desire for pure knowledge, to understand the natural world.

What are some of the greatest obstacles facing the community of researchers studying on HD? Dr. Morimoto believes that one of the most pressing questions involves the use of model systems like C. elegans, mice, or tissue culture to study HD. We can certainty understand the fundamentals of proteinfolding, aggregation, toxicity, and nerve cell death by using these model systems. However, to what extent can we take these fundamental discoveries and apply them to humans- a vastly more complex creature than mice, worms, or yeast? Dr. Morimoto believes that discoveries in model systems will prove to be useful and important because the machinery behind protein quality control is an ancient and conserved process. He believes that most of the discoveries made in less complex model systems will probably also be found in humans. However, he is concerned that researchers will have to take into account the fact that humans have very complex systems (such as human metabolism) when developing therapies. Another obstacle will be that of developing effective drug therapies. He explains that there has been limited success in discovering which proteins to target with therapeutic drugs . One in one hundred options may work, but there are not yet one hundred likely targets. In order to discover new targets, Dr. Morimoto argues that there must be more consensus among different branches of the scientific community. He strongly believes that when research laboratories partner up, they are much more effective and successful than when they work on their own.

Dr. Morimoto emphasizes that, among the myths of research that he would like to dispel, research labs like his are wonderfully diverse in their scope of cultural backgrounds, scientific experience, and intellectual perspectives. He stresses that the lab environment can be a very cooperative and social one, as opposed to the stereotype of fierce competition. Diversity and collaboration are important characteristics for successful scientific research.

-J. Seidenfeld, 3/14/06

HOPES is a team of faculty and undergraduate students at Stanford University dedicated to making scientific information about Huntington’s disease (HD) more readily accessible to the public